Acetylcholine (ACh), an essential neurotransmitter, occurs both within the brain and in the peripheral parasympathetic nervous system. Impulses conducted along muscle fibers or axons depend upon the formation of ACh at the synaptic junction for transmission of the impulse to other fibers or axons. Acetylcholine's function as a transmitter is terminated (switched off) when it is converted to choline and acetic acid by the enzyme acetylcholinesterase (ACHE). Modern bidphysical methods have revealed that the amount of time required for the process of conversion of ACh to choline and acetic acid is less than one thousandth of a second. Drugs that have the ability to inhibit or inactivate AChE are called anticholinesterases or AChE inhibitors. As a result of AChE inhibition, acetylcholine accumulates in the synaptic cleft; and since ACh is not switched off, impulses arc transmitted to the affected site for a longer period of time and causes a stronger or more prolonged neuromuscular action. Since these ACh parasympathetic synapses are widely distributed in the brain and peripheral nervous system, it is not surprising that AChE inhibitors produce a wide variety of effects on both the brain and body. Physostigmine free base is one of the naturally occurring acetylcholinesterase inhibitors. It has been isolated from the dry, ripe seed of the calabar or ordeal bean, a perennial plant (Physostigma venenosum), found in the Calabar region of Nigeria, West Africa. Also called Esre nut, chop nut or bean of Etu Esre, calabar bean was used as an ordeal poison. As a test of guilt, the suspect was forced to ingest a quantity of calabar beans. If he died, his guilt was proved. If the accused was confident of his innocence and ate the beans rapidly, the chances were high that he would regurgitate the beans and survive the ordeal. (It is reported that proof of guilt or innocence was not always left to chance. Apparently, a placebo was given to those prejudged to be innocent by the tribal elders in order to avoid any potential miscarriages of tribal justice), see "Plants in the Development on Modern Medicine", Swain, T. ed., Harvard University Press, p. 303-360 (1972). Physostigmine free base, isolated from the calabar bean, was introduced into medicine for the treatment of wide angle glaucoma in 1877 by Laqueur. Glaucoma is a disease characterized by an increase in intraocular pressure that, if sufficiently high and persistent, can lead to damage to the optic disc and result in permanent blindness. Wide angle glaucoma, or chronic, simple glaucoma occurs when the meshwork of pores of small diameter involved in the outflow of the aqueous humor lose their tone. Wide angelo glaucoma has a gradual, insidious onset and is generally not amenable to surgical improvement. In this type of glaucoma, control of ocular pressure is only possible with continuous and permanent drug therapy.
Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigability of skeletal muscles. Its clinical manifestations were described before the turn of the century, but it was not until the early 1930s that physostigmine was used in the management of this disease. The observation that physostigmine gave rise to increased strength of muscular contraction and the similarity between the symptoms of myasthenia gravis and curate poisoning in animals, suggested that physostigmine, an agent then known to antagonize curate, might be of therapeutic value for this disease. This observation led to the use of physostigmine in the treatment of myasthenia gravis.
Tardive dyskinesia is a disease characterized by abnormal, involuntary movements, usually of oral and facial musculature but often involving the trunk and extremities. Typical of oral and facial movements are puffing of the cheeks, grimacing, protrusion, and licking of the tongue, and incessant blinking of the eyes. The abnormal movements are rhythmic and repetitive and may interfere with speech, salivation, chewing, and swallowing. Patients, many times, are not aware of the symptoms. Tardive dyskinesia is usually irreversible and considered to be incurable, at the present time. Therefore, treatment of the symptoms of this disease is considered to be the only known possible therapy for dealing with the problem. Tardive dyskinesia is most frequently found in geriatric patients who have been taking neuroleptic drugs. All neuroleptic drugs have the potential to cause tardive dyskinesia. However, the low-dose, high potency drugs which produce the greatest degree of blockage, and thus a greater degree of pyramidal side effects are the most likely to cause tardive dyskinesia. Such high potency drugs include the phenothiazines, the thioxanthenes, the butyrophenones, the benxodiazepines, and the dihydroindolones. In recent years, the greater use of psychotropic drugs has aggravated the incidence of tardive dyskinesia. The increasing use of neuroleptic drugs in geriatric care facilities has resulted in dramatic increase in the incidence of tardive dyskinesia. See Geriatrics, Volume 34, Number 7, pages 59456, July 1979, by Harcourt Brace Jovanovich, Inc. An investigation in the use of anticholinergic drugs reported in American Journal of Psychiatry, Volume 134, Number 7, July 1979, pages 769-774 indicates that the use of physostigmine and choline have positive: therapeutic effect on tardive dyskinesia. Although the data presented is equivocal, tests have shown that physostigmine injections reduce tardive dyskinesia in from 20% to 80% of the patients suffering; from tardive dyskinesia. Continuous and permanent drug therapy is necessary to control tardive dyskinesia.
Senile dementia of the Alzheimer's type (SDAT) is a progressive, incurable, and irreversible disease characterized by long-term memory impairment. Studies in humans and animals have implicated cholinergic processes in memory functioning. Investigations with anticholinergics and cholinomimetics indicate that fluctuations in cholinergic activity can profoundly affect storage and retrieval of information in memory. Davis, et al in a study by reported in Science, Volume 201, p. 272 (1978) conclude that physostigmine significantly enhanced storage of information into long-term memory. This study moreover indicates that retrieval of information from long-term memory was also improved by physostigmine therapy. Treatment of tardive dyskinesia, wide angle glaucoma, SDAT, and the like, by injection of physostigmine is not a practical therapy. Physostigmine exhibits a short half-life (about 1 to 2 hours) due to rapid metabolism following systemic administration. Thus, treatment would require injections of physostigmine every 30 minutes to 1 hour, at a minimum, to maintain efficacious blood levels. Additionally, physostigmine has a narrow therapeutic window which necessitates constant patient monitoring for safety and can cause side effects which limit its systemic use. Recently, physostigmine has been formulated into tablets for oral dosage. Determination of drug blood levels for multiple oral doses show typical variations in blood concentration ranging from a maximum above the required level (and possibly in the toxic range) to a minimum which may be below the effective dose. The dysfunctions mentioned above, as well as many others, are more prevalent among the elderly. This population group endures more memory impairment and physical disability than other age groups and consistent therapy is necessarily, more difficult to attain. Percutaneous administration of physostigmine free base has many advantages over systemic therapy. It is well known that patient compliance is improved where therapy can be attained with a fewer number of drug applications within a twenty-four hour period. Transdermal administration offers the possibility that application of an appropriate device need occur but once in a twenty four hour period. Therapy can be terminated by simple removal of the transdermal device. Stable blood levels can be obtained using dose controlled devices, thus limiting the toxic side effects caused by overdosing and the lack of effect due to underdosing. Pharmacologically active agents with short metabolic lifetimes are particularly good candidates for transdermal drug delivery. The literature is filled with descriptions of devices for the slow or sustained or controlled release of medicaments. These devices may take the form of monolithic reservoir devices, osmotically driven devices, membrane controlled devices, enhancer controlled devices, microencapsulated drugs, bioerodable devices, and almost every conceivable combination of the above. For a general review of the art see, "Controlled Release of Biologically Active Agents", R. W. Baker, John Wiley and Sons, 1987. The transdermal delivery of systemically active drugs through the skin has certain constraints which limit its wider application. The main one is the need for very potent drugs, since, except for a few chemicals, the skin is a barrier to the passage of most substances. Thus, the most suitable drugs for controlled administration via this route are those active at a injectable dose of a few milligrams per day or less. Many cholinergic or anticholinergic drugs are effective at this dose range. The term "enhancer" as used herein is meant to include those chemical substances whose ultimate effect is to increase the amount of drug delivered to the host regardless of their modes of action. Reliable prediction of enhanced drug delivery for any given drug/enhancer combination is not possible as yet, because the many different factors that influence and control the permeation of chemicals through the skin are incompletely understood. At some point in time, the state of comprehension of skin/drug/enhancer interaction will be such that the performance of any given drug/enhancer combinations may be predictable from first principles but until that time, the designer of transdermal drug delivery devices must use empirically derived knowledge and examples. Leeson, in U.S. Pat. No. 4,575,539, (herein incorporated by reference), suggests the use of five chemically distinct enhancers ("azone", ethanol, dimethylsulfoxide, decyl methyl sulfoxide, and N-methyl lauramide) with four types of pharmaceutically active tertiary amines. Fischer, et al. (herein incorporated by reference), in U.S. Pat. No. 4,788,063, combines the free base form of a group of pharmaceutically active tertiary amines, almost identical to those described in Leeson above, with an excess of low molecular weight fatty acid which serves as both solvent and as transdermal delivery agent. Konno, et al. in U.S. Pat. No. 4,685,911, (herein incorporated by reference), describes the use of a suppository base, e.g. triglyceride of a vegetable saturated fatty acid having 12 to 18 carbon atoms in combination with a penetration enhancer. Our invention discloses the unexpected increase of skin permeability of a similar class of pharmaceutically active tertiary amines in their free base form through the use of fatty esters, especially isopropyl myristate and the ester of ethylene glycol and myristic acid. The term "low molecular weight" as used in reference to the ester type enhancers of this invention are defined as the reaction product of mono or difunctional functional alcohols containing 1 to 8 carbon atoms with fatty acids and are not of the triglyceride type as described by Konno, et al. in U.S. Pat. No. 4,685,911.